THE SUBTHALAMIC ACTIVITY AND STRIATAL MONOAMINE ARE MODULATED BY SUBTHALAMIC STIMULATION T. YAMAMOTO, a * T. UCHIYAMA, a R. SAKAKIBARA, b J. TANIGUCHI a AND S. KUWABARA a a Department of Neurology, Chiba University Graduate School of Medicine, Chiba, Japan b Neurology Division, Department of Internal Medicine, Sakura Medical Center, Toho University, Sakura, Japan Abstract—Aims: Not all the mechanisms by which subtha- lamic nucleus deep brain stimulation (STN-DBS) alleviates parkinsonian symptoms have been clarified as yet. The levels of striatal monoamine and the subthalamic beta activ- ity might contribute to its efficacy. However, their direct rela- tionship is unclear. We aimed to examine the correlation between the striatal monoamine and the STN beta activity induced by STN-DBS. Experimental procedures: Experiments were performed under urethane anesthesia in normal (n = 4) and 6-hydroxy- dopamine hemi-lesioned Parkinson’s disease (PD) model rats (n = 5). STN-DBS was applied to the left STN, and local field potential (LFP) was recorded before and after STN- DBS. Striatal extracellular fluid was collected before, during, and after STN-DBS. Spectral analysis of STN-LFP was per- formed, and the levels of monoamine were measured. Results: The levels of 3–4-dihydroxyphenylacetic acid (DOPAC) were significantly decreased after the cessation of stimulation in PD model rats. The levels of none of the monoamines were significantly affected in normal rats. The STN beta power was significantly elevated after the ces- sation of stimulation in normal rats but was significantly decreased in PD model rats. Results: The STN beta power and the levels of DOPAC and 5-HT was positively correlated in PD model rats, whereas the levels of dopamine and 5-HT showed positive correlation and the levels of DOPAC and Homovanillic acid (HVA) showed negative correlation in normal rats. Conclusion: STN-DBS could decrease the levels of DOPAC and the STN beta power in a PD model rat. The STN beta power and the levels of striatal monoamine might be differ- entially correlated between normal and PD model rats. Ó 2013 IBRO. Published by Elsevier Ltd. All rights reserved. Key words: Parkinson’s disease, subthalamic nucleus, deep brain stimulation, local field potential, striatal monoamine. INTRODUCTION Subthalamic nucleus deep brain stimulation (STN-DBS) is the preferred surgical therapy in patients with advanced stage of Parkinson’s disease (PD) (Benabid et al., 2009). However, its physiological mechanisms remain unclear (Perlmutter and Mink, 2006; Kringelbach et al., 2007; Humphries and Gurney, 2012). Because only high-frequency (>100 Hz) STN-DBS is clinically effective, STN-DBS has been postulated to alleviate pathological oscillation (especially that of the beta band: 15–35 Hz) in the basal ganglia of patients with PD (Brown, 2007; Eusebio et al., 2011; Giannicola et al., 2010; Hammond et al., 2007; Ray et al., 2008). Another proposed mechanism is that STN-DBS affects neurotransmitter release in the basal ganglia (Windels et al., 2003, 2005; Gubellini et al., 2009). Some studies have examined the effect of STN-DBS on striatal dopamine (DA) release (Lacombe et al., 2007; Pazo et al., 2010). Although positron emission tomography (PET) measurements of [ 11 C]raclopride uptake during STN-DBS in humans failed to demonstrate any change in striatal DA (Hilker et al., 2003), several studies using a rodent model of PD revealed that STN-DBS increased striatal DA release (Meissner et al., 2001, 2002; Lacombe et al., 2007; Paul et al., 2000; Bruet et al., 2001; Pazo et al., 2010). However, stimulation parameters varied considerably among laboratories, and whether or not STN-DBS increases striatal DA is still unknown. Despite these controversial results, it is reasonable to postulate that STN-DBS might affect striatal DA release because it is effective in patients responsive to dopaminergic treatment. Although both alleviation of pathological oscillation and influence on striatal DA release are plausible mechanisms of STN-DBS (Jenkinson and Brown, 2011), previous studies examined these issues separately. Recent review proposed the close relationships between the dopaminergic activity and beta activity in the basal ganglia, suggesting that beta activity might be elevated when the net DA level is at a low level (Jenkinson and Brown, 2011). We aimed to simultaneously examine the changes in the levels of striatal monoamine and the power in the beta activity of STN induced by STN-DBS 0306-4522/13 $36.00 Ó 2013 IBRO. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.neuroscience.2013.11.034 * Corresponding author. Address: 1-8-1 Inohana Chuo-ku, Chiba 260- 8670, Japan. Tel: +81-43-226-2129; fax: +81-43-226-2160. E-mail address: tatsuya-yamamoto@mbc.nifty.com (T. Yamamoto). Abbreviations: 5-HIAA, 5-hydroxyindoleacetic acid; 6-OHDA, 6-hydr- oxydopamine; DA, dopamine; DOPAC, 3–4-dihydroxyphenylacetic acid; EDTA, ethylenediaminetetraacetic acid; FFT, fast Fourier transform; H 2 O 2 , hydrogen peroxide; HPLC, high-performance liquid chromatography; HVA, Homovanillic acid; LFP, local field potential; PBS, phosphate-buffered saline; PBST, PBS containing 0.05% Tween- 20; PD, Parkinson’s disease; PSD, power spectral density; SNc, Substantia nigra pars compacta; STN-DBS, subthalamic nucleus deep brain stimulation. Neuroscience 259 (2014) 43–52 43